Inductive signaling plays a critical role in both normal and disease development as developmental pathways that become unregulated in the adult can lead to abnormal patterning, overproliferation and neoplasia. One signaling pathway that is involved in several patterning events during embryogenesis is that triggered by secreted sonic hedgehog (Shh.sup.1-4). Shh binding to the membrane patched (ptc)-smoothened (smo) receptor complex elicits a cascade of cytoplasmic signal transduction events, including the inhibition of protein kinase A (PKA.sup.5-12) that leads to the transcription of the zinc finger transcription factor gene Gli1.sup.11,13. Gli1 is a proto-oncogene first isolated as an amplified gene in a glioma.sup.14 that can transform fibroblasts in cooperation with E1A.sup.15. Gli1 is a member of a family comprising two other related genes: Gli2 and Gli3.sup.16,17. However, only Gli1 has been shown to be a target of Shh and mimic its effects.sup.13. In Drosophila, hedgehog signaling.sup.18 similarly leads to the action of cubitus interruptus (ci), a Gli homolog that activates transcription of hedgehog-target genes.sup.19-23.
One of the processes in which Shh signaling is involved is the differentiation of ventral neural tube cell types acting as a notochord and floor plate-derived signal.sup.1,4,24-27. Previous work by the applicants herein on the role of sonic hedgehog signaling during neural plate patterning in frog (Xenopus laevis) embryos demonstrated that cells becoming floor plate respond to Shh by expressing Gli1, Pintallavis and HNF-3.beta., critical transcription factors that themselves can induce the differentiation of floor plate cells.sup.13,25,28,29.
In addition to effects on neural tissue, it has been found that ectopic expression of Shh and Gli1 also leads to the activation of Shh signaling target genes in epidermal non-neural ectoderm. Injected Shh induced the ectopic expression of Gli1, HNF-3.beta. and Shh.sup.25, and ectopic expression of Gli1 induced the ectopic expression of HNF-3.beta. and Shh.sup.13. Together, these results indicated that both neural and epidermal cells have functional reception and transduction mechanisms for Shh and can respond by activating the expression of Shh/Gli1 target genes even though epidermal cells do not normally receive the Shh signal at this stage.
The citation of any reference herein should not be construed as an admission that such reference is available as "Prior Art" to the instant application.